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The Principal Investigators (PIs) of the National Human Genome Research Institute (NHGRI)-funded large-scale sequencing centers met with members of the Council Planning Subcommittee and NHGRI staff to discuss the critical issues in large-scale sequencing that should be taken into account in formulating the next NHGRI five-year plan. These issues included: 1) sequencing costs; 2) scale-up plans and sequencing capacity; 3) technology development; 4) the merits of centralized mapping; 5) the role of mouse sequencing; and 6) any other issues the PIs felt to be critical. The major points made by the PIs were as follows:

On the basis of progress made in the past few years, the PIs are optimistic that the human genome can be sequenced by 2005.

Current unit sequencing costs are about $0.50 per base pair. However, concern was expressed about the likelihood of continuing decreases in sequencing costs. Several PIs stated that it is not clear how the next 2-fold cost reduction, which NHGRI projections have assumed, will be achieved.

Cost accounting is difficult, but uniformity is desirable. It is apparently widely perceived that NHGRI currently focuses on a "dollars in, bases out" calculation, which the PIs think is too simplistic [staff note: this is not actually a complete description of the NHGRI approach, which does begin with "dollars in, bases out" but then goes on to ask the sequencers to back out (and therefore identify) each of those costs which are not appropriate to consider as production costs]. It was suggested that accounting procedures that break down costs according to process (for example, with "per-lane" accounting) may be more useful for assessing which parts of the process are amenable to cost decreases in each center, over the longer term. "Per-lane" accounting may also be more useful for reviewers to directly compare performance of centers.

The $60M per year that NHGRI has proposed to devote to large-scale human sequence production may not be adequate. It was argued that holding spending to this level would discourage groups from exploring more efficient ways of sequencing in the long run and does not even account for the full cost of scale-up, e.g., it does not accommodate the cost of new facilities. Some argued that, in the short term, costs may actually increase rather than decrease, particularly to maintain good quality sequence. The NHGRI cost model was also criticized for not allowing for (1) a large initial investment that may result in long range cost reductions and (2) large failures. The suggestion was made to reserve more (as much as all) of the NHGRI budget for large-scale sequencing and only funding other parts of the programs from the savings achieved by reducing sequencing costs.

Maintaining high sequence quality is challenging (and increases costs), but is critically important to the success of the project.

A number of local problems common to several centers were identified: (1) space is limiting capacity; (2) retention and training of good personnel is difficult; and (3) attracting talent to the field is difficult. The PIs suggested that these problems could be ameliorated if NHGRI were to adopt ambitious goals, beyond the human genomic sequence. This would help them convince university officials, good personnel and outside talent that there was a long-term future for the sequencing centers.

Only one center declared plans to reach a capacity of 100 Mb per year. Most of the others reported plans to scale up to 20 to 50 Mb per year (including some groups, which had been thought to have interest and potential to scale to 100 Mb per year).

There was discussion of the concept of supporting sequence-ready map production for both the human and mouse genome separately from sequence production. However, no consensus developed that the current NHGRI policy of directly linking mapping and sequencing should be changed.

Technology development is sometimes difficult in an academic environment but private industry is dissuaded from it by a perception of lack of profitability. Ambitious goals beyond completion of the human sequence may help increase enthusiasm for technology development.

Sequencing the mouse genome should be taken to be a goal of the NHGRI and should be aggressively pursued once the infrastructure for sequencing the human genome is fully funded.

Report on the Planning Meeting of the NHGRI
Large-Scale Sequencing Principal Investigators

Hyatt Regency, Bethesda
December 18, 1997

Participant List

Mark Adams, Ph.D.
The Institute for Genomic Research

Maria Athanasiou, Ph.D.
University of Texas Southwestern Medical School

Elbert Branscomb, Ph.D.
Lawrence Livermore National Laboratory

Aravinda Chakravarti, Ph.D.
Case Western Reserve University

Sandra Clifton, Ph.D.
University of Oklahoma

Francis Collins, M.D., Ph.D.
National Human Genome Research Institute

David Cox, Ph.D.
Stanford University

Pieter de Jong, Ph.D.
Roswell Park Cancer Institute

Glen Evans, M.D., Ph.D.
University of Texas Southwestern Medical School